(1) Technical Field:
The invention relates generally to controlled release drug delivery systems, and more particularly relates to bioerodible implants for controlled release of a pharmacologically active agent over an extended time period. The invention finds utility in the fields of drug delivery, pharmaceuticals, medicine, and public health.
(2) Description of Related Art:
Many individuals must take medication on a regular basis for a significant period of time. Such chronic pharmacotherapy is necessary for many different types of drugs prescribed in a wide variety of contexts, ranging from antidepressant and antipsychotic medications taken several times a day to prevent a serious mental health setback, to antiretroviral “cocktails” that require an ongoing and complicated dosage regimen to effectively treat a potentially fatal disease such as Acquired Immune Deficiency Syndrome (“AIDS”). A lack of patient compliance in such cases, including even a relatively small divergence from a prescribed dosage regimen, can adversely affect a patient's health and well being and even jeopardize a patient's life.
Furthermore, there are numerous medications that can diminish a person's ability to think clearly or adversely affect short term memory, in turn impacting on a patient's ability to follow a prescribed dosage regimen. It is well known, for example, that many life-saving cancer drugs are associated with so-called “Chemotherapy-Related Cognitive Impairments,” sometimes referred to as “chemo brain” or “chemo fog,” which reduces the likelihood that the cancer patient can adhere to a required dosage regimen.
A reliable drug delivery system for chronic administration of one or more pharmacologically active agents could overcome the problems noted above, eliminating the need for rigorous compliance with a prescribed drug dosage regimen.
Such a system would also be useful in the long-term, controlled release delivery of active agents that are commonly administered orally, as a delivery system for continuously administering a drug over a period of months, or even years, would not involve oral administration. Superior long-term drug delivery systems would thus be useful with drugs that exhibit low oral bioavailability as a result of first-pass metabolism or incomplete absorption. Drugs that exhibit a significant first pass effect include well known and often prescribed drugs such as imipramine, propranolol, buprenorphine, diazepam, cimetidine, and nitroglycerine, among others.
An effective long-term controlled release delivery system would also be useful to administer drugs that are usually given orally, but where oral administration often results in moderate to severe gastrointestinal (“GI”) side effects. For example, oral administration of nonsteroidal anti-inflammatory agents (commonly known as “NSAIDs”) is associated with numerous GI side effects that include nausea and vomiting, dyspepsia, gastric ulceration, gastric bleeding, and diarrhea. With NSAIDS, these GI side effects are due to the acidity of the drugs and to their inhibition of COX-1 and/or COX-2, a mechanism of action that reduces the amount of protective prostaglandins synthesized in the GI tract. Anti-epileptic drugs, pain drugs, and numerous other drugs that are commonly administered via the oral route are also known to result in a multitude of gastrointestinal side effects.
The idea of using implantable pellets to provide for controlled release of an active agent over an extended time period is known. In the area of contraception, for instance, drug delivery implants have been proposed as systems that would eliminate the need for daily dosing (as is required with oral contraceptive agents) and provide reliable contraceptive protection for an extended time period, e.g., a year, two years, three years, or even longer. An ideal long-term contraceptive agent would also be “forgettable” insofar as its effectiveness would not depend on user compliance each day or at each coital act; removable before complete absorption, for women who decide to terminate use of birth control; and biodegradable, so that removal is not required.
Most of the work on contraceptive implants to date has involved the use of aliphatic polyesters, including polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL) and the copolymer of PLA and PGA, poly (lactic-co-glycolic acid) (PLGA); see Pitt et al. (1981) NIDA Res. Monogr. 28:232-53. Such materials have been viewed as attractive candidates because their degradation products are naturally occurring metabolites, i.e., lactic and glycolic acid. A polycaprolactone-based contraceptive implant, Capronor™, was developed in the 1980s to release levonorgestrel for a period in the range of 12 to 18 months and then degrade. The product was ultimately abandoned, however, because of skin irritation experienced by study participants, stability problems during storage, and a long release tail, explained infra.
More recently, long-term controlled release implants have been developed for the administration of etonogestrel (Implanon®, as well as the newer radio-opaque version, Nexplanon®, from Merck & Co.). See Maddox et al. (2008) P&T 33(6):337-347, the prescribing information for Implanon and Nexplanon, and U.S. Pat. Nos. 4,957,119, 8,722,037 and 8,888,745. Like many other implants, however, Implanon and Nexplanon must be surgically removed once the active agent is depleted. The need for surgical removal of an implant is inconvenient and potentially risky; issues can arise with the formation of fibrous tissue around the implant, the failure to locate implants that may have been inserted too deeply, pain, tissue damage, local infection, and nerve damage.
In addition, many controlled release implants are associated with a long “tail period” after much of the active agent has been released, in which the implant is still releasing active agent but at a sub-effective level; see, e.g., Raymond et al. (1996) Fertil. Steril. 66(6):954-61. In the aforementioned study, involving a biodegradable implant, the dosage of the contraceptive agent fell below the minimum effective level for some time, in some cases for as long as 18 months. This is an unacceptably long time period during which contraceptive agent is still being delivered but at a dosage that is too low to provide a contraceptive effect. Other implants that are bioerodible have also resulted in significant tail period.
There is, accordingly, an ongoing need in the art for an implantable drug delivery system that provides for controlled release of an active agent throughout an extended drug delivery time period. An ideal controlled release implant would be (1) bioerodible, thereby obviating the need for surgical removal, (2) composed of non-toxic, naturally occurring materials, (3) simple, inexpensive, and straightforward to manufacture, without need for many steps, complicated equipment, toxic reagents, or a great deal of time, and (4) physically and chemically stable during storage, handling, sterilization, handling, and a possible early removal procedure. In addition, an ideal drug delivery implant would provide for controlled release of an active agent at an effective level over an extended time period, as is necessary with chronic pharmacotherapy. The ideal implant would also have a reduced tail period relative to those observed with earlier implants.